Chronic liver disease (CLD) is the 12th leading cause of mortality in the US and causes ?2 million deaths/year world-wide, making it a major health problem. Liver fibrosis contributes to the majority of clinical complications of CLD and is further on the rise due to the global epidemic of obesity and NASH. Despite identification of key pathways that promote liver fibrosis such as TGFb and PDGF, there is still not a single approved anti-fibrogenic drug for patients with liver fibrosis. On a mechanistic level, hepatocellular death is a key driver of liver disease progression, with a 6-fold higher risk for the development of cirrhosis in patients with great than two-fold increased ALT levels. Likewise, genetic induction of hepatocellular death in mice is sufficient to trigger the progression to fibrosis. However, mechanisms by which cell death promotes fibrosis remain poorly understood and therapeutically unexploited. Here, we hypothesize that damage-associated molecular patterns (DAMPs) and their receptors may provide a direct link between hepatocyte death and fibrogenesis in the liver. Such a DAMP/DAMP receptor system would endow hepatic stellate cells (HSC), the primary fibrogenic cell type in the liver, with the ability to sense liver injury via hepatocyte-released DAMPs, resulting in HSC activation and fibrogenesis as tailored response to hepatocellular injury. Based on whole genome screens, in which we identified several HSC-enriched candidate DAMP receptors, and subsequent functional in vitro and in vivo assays, our proposal will focus on P2RY14 and its ligands UDP-glucose, UDP-galactose and UDP-glucuronic acid as the candidate profibrogenic DAMP/DAMP receptor system in the liver. In Aim 1, we will investigate (i) which modes of cell death trigger activation of this DAMP/DAMP receptor system; (ii) the mechanisms by which P2RY14 and its ligands affect HSC activation, proliferation and migration; and (iii) confirm human relevance by determining P2YR14 expression and P2YR14 ligands in patients and by studying P2RY14-mediated activation of human HSC. In Aim 2, we will determine the contribution of P2RY14 to liver fibrosis with a particular focus on NASH, using HSC-specific P2RY14 deletion strategies as well as pharmacologic inhibition of P2RY14 to establish P2RY14 as potential target for antifibrogenic therapies. Together, the proposed studies will establish the new paradigm that a specific DAMP-DAMP receptor-ligand pair with cell-specific expression patterns links hepatocyte death to HSC activation and liver fibrosis, and that it may provide a novel therapeutic target for liver fibrosis. !